Meningitis‐associated hearing loss: Protection by adjunctive antioxidant therapy

Klein, Matthias; Koedel, Uwe; Pfister, Hans‐Walter; Kastenbauer, Stefan

doi:10.1002/ana.10684

Cited by 67 publications

(52 citation statements)

References 37 publications

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“…Furthermore, TLR and MyD88 knockout mice demonstrated less hearing loss following pneumococcal meningitis (247). In a rat model, cochlear expression of iNOS and eNOS was upregulated following pneumococcal meningitis, and RNS-mediated cochlear damage could be attenuated both electrophysiologically and histopathologically by RNS scavengers (227,241,243). Earlier studies with guinea pigs showed that local perfusion of the scala tympani with NO donor compounds resulted in cochlear damage and could be attenuated by NO inhibitors or O 2 scavengers (14).…”

Section: Cochlear Damage and Hearing Lossmentioning

confidence: 99%

Pathogenesis and Pathophysiology of Pneumococcal Meningitis

et al. 2011

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SUMMARY Pneumococcal meningitis continues to be associated with high rates of mortality and long-term neurological sequelae. The most common route of infection starts by nasopharyngeal colonization by Streptococcus pneumoniae , which must avoid mucosal entrapment and evade the host immune system after local activation. During invasive disease, pneumococcal epithelial adhesion is followed by bloodstream invasion and activation of the complement and coagulation systems. The release of inflammatory mediators facilitates pneumococcal crossing of the blood-brain barrier into the brain, where the bacteria multiply freely and trigger activation of circulating antigen-presenting cells and resident microglial cells. The resulting massive inflammation leads to further neutrophil recruitment and inflammation, resulting in the well-known features of bacterial meningitis, including cerebrospinal fluid pleocytosis, cochlear damage, cerebral edema, hydrocephalus, and cerebrovascular complications. Experimental animal models continue to further our understanding of the pathophysiology of pneumococcal meningitis and provide the platform for the development of new adjuvant treatments and antimicrobial therapy. This review discusses the most recent views on the pathophysiology of pneumococcal meningitis, as well as potential targets for (adjunctive) therapy.

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Section: Cochlear Damage and Hearing Lossmentioning

confidence: 99%

Pathogenesis and Pathophysiology of Pneumococcal Meningitis

et al. 2011

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“…Possibly, the difference of the power of NAC to reduce the otologic sequelae may be related to differences in the animal models used. Indeed, compared with the hearing thresholds in uninfected control animals, the hearing thresholds were elevated by 60 dB in rats with meningitis (25), whereas the hearing thresholds were up to 90 dB higher in mice with meningitis (current study). This may be related to a higher vulnerability of mice to cochlear damage, as evidenced by differences in histopathology.…”

Section: Discussionmentioning

confidence: 48%

“…For example, infected mice often develop hemorrhages in the spiral ganglion, which are usually not found in rats with pneumococcal meningitis-associated hearing loss (29,40). Also, different pneumococcal serotypes were used in the two experimental setups, namely, serotype 3 in the rat model (25) and serotype 2 in this current mouse model. As differences in pneumococcal serotype are known to account for differences in the development of hearing loss in adults with pneumococcal meningitis (41) and pathophysiologic alterations in animal models of pneumococcal meningitis (42), this may have added further to the variations seen between the two models.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, NAC was considered a promising therapeutic agent for adjunctive therapy of pneumococcal meningitis. However, long-term animal studies focusing on effects of adjunctive therapy with NAC on clinical symptoms throughout the course of the disease and after recovery are limited, and moreover, the currently published data were obtained in adult and infant rats with pneumococcal meningitis only (16,(23)(24)(25). Before experi-…”

mentioning

confidence: 99%

“…NAC, which has already been in clinical use for a long time without remarkable side effects (e.g., for therapy of acetaminophen intoxication) (20)(21)(22), was shown to reduce brain edema, intracranial pressure (ICP), and CSF pleocytosis in adult rats (16) and to attenuate cortical neuronal necrosis in infant rats during the acute stage of pneumococcal meningitis (23,24). Furthermore, an attenuation of acute and long-term hearing loss and its morphological correlates was found in rats with pneumococcal meningitis (25). Just recently, NAC was reported to reduce neurocognitive deficits in adult rats who survived experimental pneumococcal meningitis (26).…”

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confidence: 99%

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Adjunctive N -Acetyl- l -Cysteine in Treatment of Murine Pneumococcal Meningitis

Högen

Demel

Giese

et al. 2013

Antimicrob Agents Chemother

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Despite antibiotic therapy, acute and long-term complications are still frequent in pneumococcal meningitis. One important trigger of these complications is oxidative stress, and adjunctive antioxidant treatment with N-acetyl-L-cysteine was suggested to be protective in experimental pneumococcal meningitis. However, studies of effects on neurological long-term sequelae are limited. Here, we investigated the impact of adjunctive N-acetyl-L-cysteine on long-term neurological deficits in a mouse model of meningitis. C57BL/6 mice were intracisternally infected with Streptococcus pneumoniae. Eighteen hours after infection, mice were treated with a combination of ceftriaxone and placebo or ceftriaxone and N-acetyl-L-cysteine, respectively. Two weeks after infection, neurologic deficits were assessed using a clinical score, an open field test (explorative activity), a t-maze test (memory function), and auditory brain stem responses (hearing loss). Furthermore, cochlear histomorphological correlates of hearing loss were assessed. Adjunctive N-acetyl-L-cysteine reduced hearing loss after pneumococcal meningitis, but the effect was minor. There was no significant benefit of adjunctive N-acetyl-L-cysteine treatment in regard to other long-term complications of pneumococcal meningitis. Cochlear morphological correlates of meningitis-associated hearing loss were not reduced by adjunctive N-acetyl-L-cysteine. In conclusion, adjunctive therapy with N-acetyl-L-cysteine at a dosage of 300 mg/kg of body weight intraperitoneally for 4 days reduced hearing loss but not other neurologic deficits after pneumococcal meningitis in mice. These results make a clinical therapeutic benefit of N-acetyl-L-cysteine in the treatment of patients with pneumococcal meningitis questionable. Streptococcus pneumoniae is the most common etiological agent of bacterial meningitis in adults in the United States and Europe (1). Despite advanced antibiotic therapy and supportive intensive care, it still has a high case fatality rate of about 20% (2, 3). This unfavorable clinical outcome is often caused by intracranial and systemic complications, such as brain edema, hydrocephalus, cerebrovascular complications, and intracranial hemorrhage. Up to 50% of survivors suffer from long-term deficits, such as hearing loss (2, 4, 5). One reason for the development of acute and longterm intracranial and cochlear complications is collateral tissue damage from the host's own immune response, which is meant to fight the invasive pathogen. Activated immune cells and neutrophils that invade the subarachnoid space produce massive amounts of reactive oxygen (ROS) and nitrogen species (RNS), including superoxide anion (O 2 Ϫ ) and nitric oxide (NO) (6). The simultaneous production of O 2 Ϫ and NO leads to the formation of peroxynitrite (ONOO Ϫ ). ROS, RNS, and especially ONOO Ϫ can exert a variety of toxic actions, including lipid peroxidation (which leads to endothelial cell dysfunction), DNA strand breakage [followed by poly(ADP-ribose) polymerase (PARP) activation and s...

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